Spirapril: pharmacokinetic properties and drug interactions.

Spirapril is a prodrug that is converted by esterolysis to the active (but poorly absorbed) diacid spiraprilat. After intravenous infusion, the disposition of spirapril is monophasic with a terminal half-life of 20-50 minutes. Plasma clearance was 56 l/h and renal clearance was 11 l/h; the volume of distribution was 28 litres. After intravenous infusion of spiraprilat, the disposition was biphasic with half-lives of 2 hours and 35 hours, respectively. Plasma clearance of spiraprilat was 10 l/h, of which 7.6 l/h was cleared by the kidneys. The volume of distribution was 43 litres. The bioavailability of orally administered spirapril was 50% whereas the bioavailability of orally administered spiraprilat was virtually zero. There was a significant first-pass metabolism of spirapril after oral administration. The pharmacokinetics of spirapril were linear within the dose range of 6-50 mg whereas the disposition of spiraprilat was non-linear with respect to the terminal phase. Variability of the pharmacokinetic parameters of spiraprilat were significantly less than that of spirapril. Plasma concentrations of both spirapril and spiraprilat were increased by 30% in the elderly. Similarly, in patients with impaired liver function, plasma concentrations of spiraprilat were reduced by 30%. In patients with severe renal impairment, spiraprilat concentrations were significantly increased by a factor of 3-4. Spirapril showed no clinically relevant drug interactions with either glibenclamide, diclophenac, cimetidine, rifampicin, hydrochlorothiazide or nicardipine.